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Abstract Bi‐allelic variants in peroxiredoxin 3 (PRDX3) have only recently been associated with autosomal recessive spinocerebellar ataxia characterized by early onset slowly progressive cerebellar ataxia, variably associated with hyperkinetic and hypokinetic features, accompanied by cerebellar atrophy and occasional olivary and brainstem involvement. Herein, we describe a further simplex case carrying a reported PRDX3 variant as well as two additional cases with novel variants. We report the first Brazilian patient with SCAR32, replicating the pathogenic status of a known variant. All presented cases from the Brazilian and Indian populations expand the phenotypic spectrum of the disease by displaying prominent neuroradiological findings. SCAR32, although rare, should be included in the differential diagnosis of sporadic or recessive childhood and adolescent‐onset pure and complex cerebellar ataxia.

OBJECTIVE: Help the pediatrician in the suspicion of neuromuscular diseases when the child has complaints or altered findings in neuropsychomotor development, presenting one review on the topic. METHODOLOGY: Non-systematic literature review using articles published between 2015 and 2021 obtained with the terms “neuromuscular disorders” and “children”; “neuromuscular disorders” and “pediatric”; “milestones” and “delay”; “motor development” and “delay”; “development”and “neuromuscular disorders”; “neuromuscular disorder” and “evaluation”; “neuromuscular disorders” and “examination” in the Lilacs, Medline, Paho, Wholis and Scielo research bases. RESULTS: Data found in the review were compiled and divided into three topics: (1) Warning signs for neuromuscular diseases: how history and physical examination help define hypotonia and signs of muscle weakness; (2) Differential Etiological Diagnoses: most common clinical presentations and brief description of the main diseases with available therapies; and (3) Investigation of Neuromuscular Diseases: examples of situations divided between those with central or peripheral hypotonia, the use of creatine phosphokinase dosage in cases of muscle weakness and motor delay and examples of confirmatory tests of neuromuscular diseases with therapeutic possibilities. CONCLUSION: Although neuromuscular diseases are individually rare, they may have specific treatment that modifies their natural history, then the important differential diagnosis when there is a delay in neuropsychomotor development. It is imperative that the pediatrician, as a reference professional for families, have a high degree of suspicion and knowledge that allows initial assessment and referral to a specialized service.

ABSTRACT A total of 1.67 million breast cancer cases per year are reported worldwide. Of these, 5%–10% are caused by inherited mutations. Phenocopy is a rare phenomenon, with only a few cases reported in the literature. In phenocopies, phenotypes identical to those with genetic origin occur because of environmental factors rather than familial mutations. We describe a case of phenocopy in a 44-year-old female patient with triple-negative breast cancer. The mother and sister wee heterozygous for c.1813delA, p.Ile605TyrfsTer9 in BRCA2 . The patient underwent genetic testing for BRCA1 and BRCA2 and exome sequencing. Familial or other cancer variants were not detected. The most accepted phenocopy theory is that patients without genetic variants but who are carriers of these mutations undergo cellular changes due to environmental factors, increasing the risk of breast cancer. Therefore, the detection of phenocopy in patients with breast cancer is important in clinical practice.

ABSTRACT Objective: To report a rare case of a patient with a molecular diagnosis of Kleefstra syndrome (KS) who has four other chromosomal alterations involving pathogenic variants. Case description: Male patient, two years old, with global delay, including in neuropsychomotor development, ocular hypertelorism, broad forehead, brachycephaly, hypotonia, ligament laxity, unilateral single palmar crease and arachnoid cyst. The microarray-based comparative genomic hybridization (a-CGH) identified copy number variations (CNVs) in five regions: 9q34.3, 6p22.1, Yq11.223, Yp11.23, and 2q24.1. The heterozygous microdeletion in 9q34.3 involving the EHMT1 gene confirms the diagnosis of KS. Comments: The presence of pathogenic CNVs and/or those of uncertain significance, located on chromosomes 2, 6 and Y, may be contributing to a variability in the patient's clinical condition (arachnoid cyst, single palmar fold and ligament laxity), compared to other individuals with only KS genetic alteration, making the dignosis of the disease harder.

ABSTRACT Objective: Autism spectrum disorder (ASD) affects cognitive development and social interaction on different levels. Genetic and environmental factors are associated with secondary ASD. Genetic inheritance is mainly polygenic, and 10% are copy number variations (CNVs). Array comparative genomic hybridization (array-CGH) is used to identify CNVs. This report aimed to discuss autism spectrum disorder and its diagnosis by array comparative genomic hybridization, highlighting the association with the pathogenic duplication of 17q12q21.2. Case description: A male baby was born at 37 weeks’ gestation by cesarean section. The child showed strabismus, cryptorchidism, hypertelorism, frontal bossing, and developmental delay, walking at 25 months and talking at 4 years. At the age of 2 years, array-CGH of peripheral blood revealed a 5.6-Mb 17q12q21.2 duplication or arr 17q12q21.2 (34,815,527-40,213.109)x3 encompassing 190 genes, including HNF-1B and LHX1. The child was clinically diagnosed with ASD. Comments: Changes in the 17q12 segment, such as the duplication found, have been associated with the development of several problems in previous studies, mainly kidney diseases and behavioral disorders. Located at this chromosome region, HNF1's homeobox B codes a member of the superfamily containing homeodomain of transcription factors. Another gene associated with abnormalities in neurological development regarding 17q12 deletions is LHX1, as shown in this case study. LHX1 plays a role in the migration and differentiation of GABA neurons, modulating the survival of pre-optical interneurons, thus affecting cellular migration and distribution in the cortex. Changes in this control result in flaws in interneuron development, contributing to the pathophysiology of psychiatric diseases.

Objective: This narrative, non-systematic review provides an update on the genetic aspects of the SARS-CoV-2 virus and its interactions with the human genome within the context of COVID-19. Although the main focus is on the etiology of this new disease, the genetics of SARS-CoV-2 impacts prevention, diagnosis, prognosis, and the development of therapies. Data source: A literature search was conducted on MEDLINE, BioRxiv, and SciELO, as well as a manual search on the internet (mainly in 2019 and 2020) using the keywords “COVID-19,” “SARS-CoV-2,” “coronavirus,” “genetics,” “molecular,” “mutation,” “vaccine,” “Brazil,” “Brasil,” and combinations of these terms. The keywords “Brazil” and “Brasil” were used to find publications that were specific to the Brazilian population’s molecular epidemiology data. Articles most relevant to the scope were selected non-systematically. Data synthesis: A number of publications illustrate an expanding knowledge on the genetics and genomics of SARS-CoV-2 and its implications for understanding COVID-19. Conclusions: Knowledge of the SARS-CoV-2 genome sequence permits an in-depth investigation of the role its proteins play in the pathophysiology of COVID-19, which in turn will be enormously valuable for understanding the evolutionary, clinical, and epidemiological aspects of this disease and focusing on prevention and treatment.

ABSTRACT Autosomal dominant cerebellar ataxias (ADCA) are heterogeneous diseases with a highly variable phenotype and genotype. They can be divided into episodic ataxia and spinocerebellar ataxia (SCA); the latter is considered the prototype of the ADCA. Most of the ADCA are caused by polyglutamine expansions, mainly SCA 1, 2, 3, 6, 7, 17 and Dentatorubral-pallidoluysian atrophy (DRPLA). However, 30% of patients remain undiagnosed after testing for these most common SCA. Recently, several studies have demonstrated that the new generation of sequencing methods are useful for the diagnose of these patients. This review focus on searching evidence on the literature, its usefulness in clinical practice and future perspectives.

Background: The spinocerebellar ataxias (SCAs) are a group of autosomal dominant degenerative diseases characterized by cerebellar ataxia. Classified according to gene discovery, specific features of the SCAs – clinical, laboratorial, and neuroradiological (NR) – can facilitate establishing the diagnosis. The purpose of this study was to review the particular NR abnormalities in the main SCAs. Methods: We conducted a literature search on this topic. Results: The main NR characteristics of brain imaging (magnetic resonance imaging or computerized tomography) in SCAs were: (1) pure cerebellar atrophy; (2) cerebellar atrophy with other findings (e.g., pontine, olivopontocerebellar, spinal, cortical, or subcortical atrophy; “hot cross bun sign”, and demyelinating lesions); (3) selective cerebellar atrophy; (4) no cerebellar atrophy. Discussion: The main NR abnormalities in the commonest SCAs, are not pathognomonic of any specific genotype, but can be helpful in limiting the diagnostic options. We are progressing to a better understanding of the SCAs, not only genetically, but also pathologically; NR is helpful in the challenge of diagnosing the specific genotype of SCA.

Certain combinations of common variants in exon 3 of OPN1LW and OPN1MW, the genes encoding the apo-protein of the long- and middle-wavelength sensitive cone photoreceptor visual pigments in humans, induce splicing defects and have been associated with dyschromatopsia and cone dysfunction syndromes. Here we report the identification of a novel exon 3 haplotype, G-C-G-A-T-T-G-G (referring to nucleotide variants at cDNA positions c.453, c.457, c.465, c.511, c.513, c.521, c.532, and c.538) deduced to encode a pigment with the amino acid residues L-I-V-V-A at positions p.153, p.171, p.174, p.178, and p.180, in OPN1LW or OPN1MW or both in a series of seven patients from four families with cone dysfunction. Applying minigene assays for all observed exon 3 haplotypes in the patients, we demonstrated that the novel exon 3 haplotype L-I-V-V-A induces a strong but incomplete splicing defect with 3–5% of residual correctly spliced transcripts. Minigene splicing outcomes were similar in HEK293 cells and the human retinoblastoma cell line WERI-Rb1, the latter retaining a cone photoreceptor expression profile including endogenous OPN1LW and OPN1MW gene expression. Patients carrying the novel L-I-V-V-A haplotype presented with a mild form of Blue Cone Monochromacy or Bornholm Eye Disease-like phenotype with reduced visual acuity, reduced cone electroretinography responses, red-green color vision defects, and frequently with severe myopia.

Background: Huntington's disease (HD) is a progressive disorder characterized by motor, cognitive and psychiatric features. Cerebellar ataxia is classically considered as uncommon in HD clinical spectrum.Objective: To determine the prevalence of cerebellar ataxia in patients with HD, both in the early and in the late stages of HD.Methods: Seventy-two individuals considered eligible were assessed by two trained doctors, applying the Scale for Assessment and Rating of Ataxia (SARA) and Brief Ataxia Rating Scale (BARS) for ataxia, the Unified Huntington's Disease Rating Scale (UHDRS) and also, Barthel Index (BI), in order to evaluate functional capacity.Results: Fifty-one patients (70.8%) presented with clinical ataxia at the time of examination (mean time of disease was 9.1 years). Six (8.33%) patients presented with cerebellar ataxia as first symptom. When stratified according to time of disease, a decline in the presence of chorea (p = 0.032) and an increase in cognitive deficit (p = 0.023) were observed in the patients as the disease progressed. The presence of ataxia was associated with longer duration of illness and severity of illness (UHDRS) (p < 0.0001), and shorter Barthel (less functionality) (p = 0.001).Conclusions: Cerebellar involvement may play an important role in natural history of brain degeneration in HD. The presence of cerebellar ataxia in HD is relevant and it may occur even in early stages, and should be included as part of the motor features of the disease.

Abstract Background Townes-Brocks syndrome (TBS) is a rare autosomal dominant condition characterized by renal, anal, limb, and auditory abnormalities. TBS diagnosis can be challenging in settings where genetic analysis is not readily available. TBS traits overlap with those of Goldenhar and VACTERL syndromes. Case presentation Here, we present the case of a 5-year-old Brazilian boy born with an anorectal abnormality, limb and external ears malformations, genitourinary anomalies, and a congenital heart defect. Genetic analysis revealed a SALL1 nonsense mutation. The case is discussed in the context of the current literature. Conclusions Because of the variability in TBS clinical presentation, genetic analysis is key to the differential diagnosis of TBS relative to phenotypically similar syndromes.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder marked by impairments in social functioning, language, communication, and behavior. Recent genome-wide association studies show some microdeletions on the 7q31-32 region, including the CADPS2 locus in autistic patients. This paper reports the case of a patient with ASD and recurrent psychotic syndrome, in which a deletion on the 7q31-32 band at the CADPS2 gene locus was evidenced, as well as a brief review of the literature on the CADPS2 gene and its association with ASD.

Several genes have been mapped in families or in sporadic cases of dystonia. TOR1-A (DYT1) gene was linked to isolated dystonia. Objective To associate clinical information of patients with dystonia with the TOR1-A gene mutations. Method Eighty-eight patients with dystonia in cervical area (focal, segmental, multifocal and generalized) were recruited at Movement Disorders Clinic of Hospital de Clínicas of the Federal University of Paraná between June of 2008 and June of 2009. They were submitted to the clinical evaluation. DNA was extract from blood and submitted at analysis to TOR1-A mutations by PCR according standard protocols. Results Two patients had c.907GAGdel mutation on TOR1-A gene. These patients, with familial history of dystonia, started his symptoms by legs and had secondary generalization. Conclusion We can suggest that analysis for TOR1-A mutations should be performed only in patients with early onset, generalized and familial dystonia.

Spinocerebellar ataxia type 3 (SCA3) involves cerebellar, pyramidal, extrapyramidal, motor neuron and oculomotor systems with strong phenotypic heterogeneity, that lead us to classify the disorder into different clinical subtypes according to the predominantly affected motor systems. Method The series comprises 167 SCA3 patients belonging to 68 pedigrees, studied from 1989-2013. These patients were categorized into seven different subphenotypes. Results SCA3 cases were clustered according to the predominant clinical features. Three most common forms were subphenotype 2, characterized by ataxia and pyramidal symptom was observed in 67.5%, subphenotype 3 with ataxia and peripheral signs in 13.3%, and subphenotype 6 with pure cerebellar syndrome in 7.2%. Conclusion Our study was the first to systematically classify SCA3 into seven subphenotypes. This classification may be particularly useful for determination of a more specific and direct phenotype/genotype correlation in future studies.

The aim of the study was to analyze a series of Brazilian patients with Niemann-Pick disease type C (NP-C). Method Correlations between clinical findings, laboratory data, molecular findings and treatment response are presented. Result The sample consisted of 5 patients aged 8 to 26 years. Vertical supranuclear gaze palsy, cerebellar ataxia, dementia, dystonia and dysarthria were present in all cases. Filipin staining showed the “classical” pattern in two patients and a “variant” pattern in three patients. Molecular analysis found mutations in the NPC1 gene in all alleles. Miglustat treatment was administered to 4 patients. Conclusion Although filipin staining should be used to confirm the diagnosis, bone marrow sea-blue histiocytes often help to diagnosis of NP-C. The p.P1007A mutation seems to be correlated with the “variant” pattern in filipin staining. Miglustat treatment response seems to be correlated with the age at disease onset and disability scale score at diagnosis.

Cervical dystonia (CD) affects the musculature of the neck in a focal way or associated to other parts of the body. The aim of this study was to identify clinical differences between patients with dystonia patients without family history and with family history (sporadic). Eighty-eight patients with CD were recruited in a Movement Disorders Clinic between June of 2008 and June of 2009. Only patients with no etiological diagnosis were accepted for analysis. The age of onset of symptoms was later in patients with focal and segmental dystonia than in patients with generalized dystonia (p

Spinocerebellar ataxia type 10 (SCA10) is a rare form of autosomal dominant ataxia found predominantly in patients from Latin America with Amerindian ancestry. The authors report the history of SCA10 families from the south of Brazil (the states of Paraná and Santa Catarina), emphasizing the Belgian-Amerindian connection.

OBJECTIVE: Wilson's disease (WD) is an inborn error of metabolism caused by abnormalities of the copper-transporting protein encoding gene ATP7B. In this study, we examined ATP7B for mutations in a group of patients living in southern Brazil. METHODS: 36 WD subjects were studied and classified according to their clinical and epidemiological data. In 23 subjects the ATP7B gene was analyzed. RESULTS: Fourteen distinct mutations were detected in at least one of the alleles. The c.3207C>A substitution at exon 14 was the most common mutation (allelic frequency=37.1%) followed by the c.3402delC at exon 15 (allelic frequency=11.4%). The mutations c.2018-2030del13 at exon 7 and c.4093InsT at exon 20 are being reported for the first time. CONCLUSION: The c.3207C>A substitution at exon 14, was the most common mutation, with an allelic frequency of 37.1%. This mutation is the most common mutation described in Europe.

CONTEXT Diastrophic dysplasia is a type of osteochondrodysplasia caused by homozygous mutation in the gene DTDST (diastrophic dysplasia sulfate transporter gene). Abnormalities occurring particularly in the skeletal and cartilaginous system are typical of the disease, which has an incidence of 1 in 100,000 live births. CASE REPORT The case of a pregnant woman, without any consanguineous relationship with her husband, whose fetus was diagnosed with skeletal dysplasia based on ultrasound findings and DNA tests, is described. An obstetric ultrasound scan produced in the 16th week of gestation revealed characteristics that guided the clinical diagnosis. Prominent among these characteristics were rhizomelia of the lower and upper limbs (shortening of the proximal portions) and mesomelia (shortening of the intermediate portions). Both upper limbs showed marked curvature, with the first finger of the upper limbs in abduction and clinodactyly of the fifth finger. Molecular analysis using the polymerase chain reaction (PCR) and gene sequencing detected mutations that had already been described in the literature for the gene DTDST, named c.862C > T and c.2147_2148insCT. Therefore, the fetus was a compound heterozygote, carrying two different mutations. CONCLUSIONS Prenatal diagnosis of this condition allowed a more realistic interpretation of the prognosis, and of the couple's reproductive future. This case report shows the contribution of molecular genetics towards the prenatal diagnosis, for which there are few descriptions in the literature. CONTEXTO A displasia diastrófica é uma osteocondrodisplasia causada por mutação homozigótica no gene DTDST (diastrophic dysplasia sulfate transporter gene). As alterações, principalmente nos sistemas esquelético e cartilaginoso, são típicas dessa doença, que tem uma incidência de 1 em 100.000 nascidos vivos. RELATO DO CASO Descreve-se o caso de uma mulher gestante, sem relação consanguínea com o seu marido, cujo feto foi diagnosticado com displasia esquelética baseado na ultrassonografia e em testes de DNA. A ultrassonografia obstétrica, realizada na 16a semana, revelou características que guiaram o diagnóstico clínico. Entre elas, se destacam os membros inferiores e superiores com rizomelia (encurtamento das porções proximais) e mesomelia (encurtamento das porções intermediárias), ambos os membros superiores mostraram acentuada flexão, o primeiro dedo em abdução nas extremidades superiores e clinodactilia do quinto dedo. A análise molecular pela reação em cadeia da polimerase (PCR) e o sequenciamento gênico detectou mutações já descritas na literatura para o gene DTDST, chamado c.862C > T e c.2147_2148insCT. Portanto, o feto é um heterozigoto composto, carreando duas mutações diferentes. CONCLUSÕES O diagnóstico pré-natal dessa condição permite uma interpretação mais realista do prognóstico e do futuro reprodutivo do casal. Este relato de caso mostra a contribuição da genética molecular no diagnóstico pré-natal, com poucas descrições na literatura.

OBJETIVO: Fissura labial com ou sem fissura palatina (FL ± P) ou fissura palatina (FP) são grupos de malformações chamados fissuras orofaciais (FO) e são a segunda causa de defeitos congênitos. O objetivo do estudo foi analisar características clínicas e epidemiológicas de pacientes brasileiros com FO, estudando casos tratados no centro de referência do estado do Paraná (PR). MÉTODOS: Foram analisados 2.356 gráficos. Destes, 1.838 foram avaliados pelo mesmo geneticista clínico. Os dados foram coletados no centro de referência e analisados na Secretaria de Estado da Saúde do Paraná. Foram avaliadas as características clínicas, a presença de outras anomalias e a prevalência de nascimentos. RESULTADOS: No total, 389 (21,2%) pacientes apresentaram fissura palatina (FP), 437 (23,8%) apresentaram fissura labial (FL) e 1.012 (55%) apresentaram fissura labiopalatina (FLP). As FO sindrômicas foram identificadas em 15,3% dos pacientes, 10,4% dos pacientes com FL ± P, e 33,9% dos pacientes com FP. Anomalias comuns adicionais foram: sistema nervoso central, membros, sistema cardiovascular e sistema musculoesquelético. O número de casos sindrômicos foi menor nos centros em que a avaliação clínica foi realizada por outros especialistas, em comparação aos locais em que ela foi realizada por um geneticista clínico. A prevalência de nascimentos foi de 1/1.010 nascidos vivos. A ausência de notificação junto ao cartório de registro civil foi observada em 49,9% dos casos de FL ± P. No Brasil, nossos dados sugerem uma redução de 18,52% na prevalência de FO não sindrômicas após a fortificação com ácido fólico. CONCLUSÃO: Um melhor entendimento dos aspectos clínicos e epidemiológicos das FO é fundamental para melhorar a compreensão de sua patogênese, promover estratégias de prevenção e promover orientações com relação a cuidados clínicos, com a presença de geneticistas clínicos na equipe multidisciplinar para tratamento de FO, por exemplo.OBJECTIVE: Cleft lip with or without cleft palate (CL±P) or cleft palate (CP) are groups of malformations named orofacial clefts (OC), which are the second leading cause of birth defects. This study aimed to analyze clinical and epidemiological features of Brazilian patients with OC, studying cases treated in the reference center of the state of Paraná (PR). METHODS: 2,356 charts were reviewed and 1,838 were evaluated by the same clinical geneticist. Data were collected in the reference center, and compared with those of the Health Department of the state of Paraná. Clinical characteristics, presence of other anomalies, and birth prevalence were evaluated. RESULTS: 389 (21.2%) patients had CP, 437 (23.8%) had cleft lip (CL), and 1,012 (55%) had cleft lip and palate (CLP). Syndromic OC were identified in 15.3% of patients, 10.4% of patients with CL±P, and 33.9% of patients with CP. Common additional anomalies were: central nervous system, limbs, cardiovascular, and musculoskeletal defects. The number of syndromic cases was lower when clinical evaluation was performed by other medical specialists when compared to that of the clinical geneticist. Birth prevalence was 1/1,010 live births. Lack of notification with the national birth registry was observed in 49.9% of CL±P. The present data suggests a decrease of 18.52% in the prevalence of non-syndromic OC after folic acid fortification in Brazil. CONCLUSIONS: Better understanding of clinical and epidemiological aspects of OC is crucial to improve the understanding of pathogenesis, promote preventive strategies, and guide clinical care, including the presence of clinical geneticists in the multidisciplinary team for OC treatment.

Objective: : Cleft lip with or without cleft palate (CL±P) or cleft palate (CP) are groups of malformations named orofacial clefts (OC), which are the second leading cause of birth defects. This study aimed to analyze clinical and epidemiological features of Brazilian patients with OC, studying cases treated in the reference center of the state of Paraná (PR). Methods: : 2,356 charts were reviewed and 1,838 were evaluated by the same clinical geneticist. Data were collected in the reference center, and compared with those of the Health Department of the state of Paraná. Clinical characteristics, presence of other anomalies, and birth prevalence were evaluated. Results: : 389 (21.2%) patients had CP, 437 (23.8%) had cleft lip (CL), and 1,012 (55%) had cleft lip and palate (CLP). Syndromic OC were identified in 15.3% of patients, 10.4% of patients with CL±P, and 33.9% of patients with CP. Common additional anomalies were: central nervous system, limbs, cardiovascular, and musculoskeletal defects. The number of syndromic cases was lower when clinical evaluation was performed by other medical specialists when compared to that of the clinical geneticist. Birth prevalence was 1/1,010 live births. Lack of notification with the national birth registry was observed in 49.9% of CL±P. The present data suggests a decrease of 18.52% in the prevalence of non-syndromic OC after folic acid fortification in Brazil. Conclusion: : Better understanding of clinical and epidemiological aspects of OC is crucial to improve the understanding of pathogenesis, promote preventive strategies, and guide clinical care, including the presence of clinical geneticists in the multidisciplinary team for OC treatment.

OBJECTIVE: Spinocerebellar ataxias are neurodegenerative disorders involving the cerebellum and its connections. There are more than 30 distinct subtypes, 16 of which are associated with an identified gene. The aim of the current study was to evaluate a large group of patients from 104 Brazilian families with spinocerebellar ataxias. METHODS: We studied 150 patients from 104 families with spinocerebellar ataxias who had received molecular genetic testing for spinocerebellar ataxia types 1, 2, 3, 6, 7, 8, 10, 12, 17, and dentatorubral-pallidoluysian atrophy. A statistical analysis of the results was performed using basic descriptive statistics and the correlation coefficient (r), Student's t-test, chi-square test, and Yates' correction. The statistical significance level was established for p-values

The Peutz-Jeghers syndrome (PJS) is an autosomal-dominant hamartomatous polyposis syndrome characterized by mucocutaneous pigmentation, gastrointestinal polyps and the increased risk of multiple cancers. The causative point mutation in the STK11 gene of most patients accounts for about 30% of the cases of partial and complete gene deletion. This is a report on a girl with PJS features, learning difficulties, dysmorphic features and cardiac malformation, bearing a de novo 1.1 Mb deletion at 19p13.3. This deletion encompasses at least 47 genes, including STK11. This is the first report on 19p13.3 deletion associated with a PJS phenotype, as well as other atypical manifestations, thereby implying a new contiguous gene syndrome.

Spinocerebellar ataxia type 6 (SCA 6) is an autosomal dominant cerebellar ataxia caused by CAG repeat expansion in the SCA6 gene, a alpha 1A voltage-dependent calcium channel subunit gene on chromosome 19p13. SCA-6 is characterized predominantly by slowly progressive pure cerebellar ataxia with late onset. We report three index patients, with pure, late onset, cerebellar ataxia, belonging to three different Brazilian families, all of them with Japanese ancestry, from Hokkaido island of Japan.Ataxia espinocerebelar tipo 6 (AEC6) é uma ataxia cerebelar autossômica dominante causada por uma expansão repetida do tripleto CAG no gene da AEC, que é uma sub-unidade do canal de cálcio voltagem-dependente alfa1A localizada no cromossomo 19p13. A AEC6 é caracterizada predominantemente por quadro de ataxia cerebelar pura, com início tardio, e evolução lentamente progressiva. Relatamos três pacientes índices, com ataxia cerebelar pura, de início tardio, pertencentes a três diferentes famílias brasileiras, todas com ancestrais japoneses, oriundas da ilha de Hokkaido.

The authors report the history of spinocerebellar ataxia 10 (SCA10), since its first report in a large Portuguese-ancestry Family with autosomal dominant pure cerebellar ataxia, till the final identification of further families without Mexican ancestry. These families present a quite different phenotype from those SCA10 families described in Mexico.Os autores apresentam a história da descoberta da ataxia espinocerebelar tipo 10 (AEC10) no Brasil, desde o primeiro relato em uma família com ancestrais portugueses com ataxia cerebelar pura, autossômica dominante, até a identificação de famílias sem ancestrais mexicanos. Essas famílias apresentam um fenótipo de AEC10, com ataxia cerebelar "pura", distinta daquele descrito nas famílias no México.

We describe seven patients with genetically confirmed Huntington's disease (HD) who had non-choreic movement disorders as presenting symptoms or signs. Patients with movement disorders other than chorea in the early stages tended to have larger CAG trinucleotide repeat expansion in comparison with more "typical" HD patients.Nós descrevemos sete pacientes com doença de Huntington, geneticamente confirmada, cuja apresentação motora inicial foi diferente de coréia. Pacientes com manifestação motora inicial diferente de coréia apresentaram maior número de expansões repetidas de CAG trinucleotídeo quando comparados com aqueles com sintomatologia motora "típica".

BACKGROUND: Rett syndrome (RS) is recognized as a pan-ethnic condition. Since the identification of mutations in the MECP2 gene, more patients have been diagnosed, and a broad spectrum of phenotypes has been reported. There is a lack of phenotype-genotype studies. OBJECTIVE: To describe two cases of Brazilian patients with identified MECP2 mutations. METHOD: We present two female Brazilian patients with RS. RESULTS: Both patients presented with regression at 2-3 years of age, when stereotypic hand movements, social withdrawal and postnatal deceleration of head growth rate were observed. Both patients presented verbal communication impairment. Case 1 had loss of purposeful hand movements, and severe seizure episodes. Case 2 had milder impairment of purposeful hand movements, and no seizures. They had different mutations, D97Y and R294X, found in exons 3 and 4 of MECP2 gene, respectively. CONCLUSION: Testing for MECP2 mutations is important to confirm diagnosis and to establish genotype/phenotype correlations, and improve genetic counseling.CONTEXTO: Síndrome de Rett (RS) é doença pan-étnica de fenótipo bastante variado desde que foram identificadas mutações no gene MECP2 e um número maior de pacientes tem sido diagnosticadas. Existe uma demanda por estudos que investiguem a relação genótipo-fenotipo. OBJETIVO: Descrever dois casos brasileiros de RS com mutações identificadas. MÉTODO: Duas pacientes brasileiras com diagnóstico clínico-molecular de RS foram descritas buscando-se correlacionar genótipo-fenótipo. RESULTADOS: Ambas pacientes apresentaram regressão aos 2-3 anos de idade, movimentos esteriotipados de mãos, retraimento social e desaceleração do crescimento encefálico. Ambas apresentaram déficit de comunicação verbal. Caso 1 também apresentou perda dos movimentos manuais intencionados e crises convulsivas graves. Caso 2 apresentou-se com comprometimento parcial dos movimentos manuais e sem história de crise convulsiva. As mutações distintas, D97Y e R294X, foram encontradas respectivamente em exons 3 e 4 do gene MECP2. CONCLUSÃO: A investigacao de mutações no gene MECP2 é importante na confirmação diagnóstica, investigação genótipo-fenótipo, e aconselhamento genético em síndrome de Rett.

Objective To investigate the relevance of the clinical finding of bulging eyes (BE) in a large Brazilian cohort of spinocerebellar ataxias (SCA), to assess its importance in clinical differential diagnosis among SCA. Methods Three hundred sixty-nine patients from 168 Brazilian families with SCA were assessed with neurological examination and molecular genetic testing. BE was characterized by the presence of eyelid retraction. Genetically ascertained SCA3 was detected in 167 patients, SCA10 in 68 patients, SCA2 in 20, SCA1 in 9, SCA7 in 6, and SCA6 in 3 patients. Results BE was detected in 123 patients with SCA (33.3%), namely 109 of the 167 SCA3 patients (65.3%) and in 5 of the others SCA patients (1 SCA10 patient, 2 SCA1 patients and 2 SCA2 patients). Conclusion BE was detected in the majority of patients with SCA3 (65.3%) and could be used with a clinical tool for the differential diagnosis of SCA.

Cerebrotendinous xanthomatosis is a treatable rare autossomal recessive disease characterized by lipid storage secondary to a sterol 27-hydroxylase deficiency in the formation of cholic and chenodeoxycholic acids. We describe two Brazilian brothers with cognitive impairement and chronic diarrhea. One of them also presents bilateral cataracts. Neurological findings were progressive walking deficit, limb ataxia and pyramidal signs. Both patients had bilateral Achilles tendon xanthomata. Magnetic resonance image showed signal alterations in cerebellar hemispheres. We describe these cases with molecular genetic analysis confirming diagnosis and comparing with previous literature. The CYP27A1 gene study showed a C1187T mutation on exon 6.Xantomatose cerebrotendínea é doença autossômica recessiva tratável causada pelo acúmulo de lipídeos por deficiência da enzima 27-esterol hidroxilase na produção de ácido cólico e deoxicólico. Descrevemos dois irmãos brasileiros com dificuldade cognitiva e diarréia crônica. Um deles apresentava catarata bilateral. Os achados neurológicos foram dificuldade progressiva para deambular, ataxia de membros e sinais piramidais. Ambos tinham xantomas de tendão aquileu bilateralmente. O exame de ressonância magnética revelou áreas de sinal hiperintenso em ambos os hemisférios cerebelares. Descrevemos os casos com diagnóstico genético comparando-os com a literatura. O estudo do gene CYP27A1 demonstrou a mutação C1183T no exon 6.

OBJECTIVE: To study tremor in patients with X-linked recessive spinobulbar muscular atrophy or Kennedy's disease. METHODS: Ten patients (from 7 families) with a genetic diagnosis of Kennedy's disease were screened for the presence of tremor using a standardized clinical protocol and followed up at a neurology outpatient clinic. All index patients were genotyped and showed an expanded allele in the androgen receptor gene. RESULTS: Mean patient age was 37.6 years and mean number of CAG repeats 47 (44-53). Tremor was present in 8 (80%) patients and was predominantly postural hand tremor. Alcohol responsiveness was detected in 7 (88%) patients with tremor, who all responded well to treatment with a β-blocker (propranolol). CONCLUSION: Tremor is a common feature in patients with Kennedy's disease and has characteristics similar to those of essential tremor.

Background: Several genes associated with dystonia have been identified. A mutation in one of these, THAP1 (DYT6), is linked to isolated dystonia. The aim of this study was to assess the prevalence of THAP1 gene mutations and the clinical characteristics of patients with these mutations in a clinical population in Brazil.Methods: Seventy‐four patients presenting with dystonia involving the cervical muscles and without mutations in the TOR1A (DYT1) gene or any other movement disorders were recruited at a movement disorders clinic between June 2008 and June 2009. All the patients underwent clinical examination and were screened for mutations of the THAP1 gene.Results: Three patients had the novel p.Gln97Ter THAP1 nonsense mutation in heterozygosis. One of them had no family history of dystonia. Symptoms in this patient first appeared in his right arm, and the condition progressed to the generalized form. The other two patients belonged to the same family (cousins). Symptoms in the first patient started in her right arm at the age of 18 years and the condition progressed to the segmental form. The second patient, who carried the p.Arg169Gln missense mutation, developed dystonia in her left arm at the age of 6 years. The condition progressed to generalized dystonia.Discussion: We conclude that THAP1 mutations are also a cause, albeit uncommon, of segmental and generalized dystonia in the Brazilian population.

We report the case of a 3-1/2-year-old girl with hypotonia, multiple joint contractures, hip luxation, arachnodactyly, adducted thumbs, dolichostenomelia, and abnormal external ears suggesting the diagnosis of congenital contractural arachnodactyly (CCA). The serum muscle enzimes were normal and the needle electromyography showed active and chronic denervation. The muscle biopsy demonstrated active and chronic denervation compatible with spinal muscular atrophy. Analysis of exons 7 and 8 of survival motor neuron gene through polymerase chain reaction did not show deletions. Neurogenic muscular atrophy is a new abnormality associated with CCA, suggesting that CCA is clinically heterogeneous.

A Cútis laxa é uma doença rara, hereditária ou adquirida. Resulta da alteração do tecido elástico, tornando a pele frouxa e inelástica. A forma congênita tem geralmente acometimento sistêmico, com pior prognóstico. Os autores relatam o caso de uma paciente, com quadro clínico sugestivo da forma hereditária da doença, com pais consangüíneos (primos de 2º grau) e irmão falecido com clínica semelhante. O estudo genético do gene FBLN5 teve importância na confirmação diagnóstica, na definição do prognóstico e no aconselhamento genético familiar.Cutis laxa is a rare inherited or acquired disorder of elastic tissue characterized by inelastic and loose skin. Congenital cutis laxa may present with internal organ involvement, determining a worse prognosis. The authors present the case of a female patient with clinical manifestations suggestive of the hereditary form of the disease, with consanguineous parents (second-degree cousins) and a brother who died with a similar clinical presentation. The genetic study of the FBLN5 gene was important to confirm the diagnosis, define the prognosis, and provide genetic counseling to the family.

The mutation in the hypoxanthine-guanine phosphoribosyltransferase (HPRT) gene has been determined in two brothers affected with Lesch-Nyhan syndrome. Female members of the family who are at risk for being heterozygous carriers of the HPRT mutation were also studied to determine whether they carry the mutation. DNA sequencing revealed that the boys' mother is heterozygous for the mutation in her somatic cells, but that three maternal aunts are not heterozygous. Such carrier information is important for the future pregnancy plans of at-risk females. The mutation, an A-->T transversion at cDNA base 590 (590A-->T), results in an amino acid change of glutamic acid to valine at codon 197, and has not been reported previously in a Lesch-Nyhan syndrome male. This mutation is designated HPRT Brasil.

We screened 79 southern Brazilian patients with cystic fibrosis for the rare cystic fibrosis mutations R1162X and 2183AA®G. Forty-nine patients were born in the State of Paraná (PR) and 30 in the State of Santa Catarina (SC). Two 2183AA®G alleles were found among the SC patients and one among the PR patients. Six R1162X alleles were found among the SC patients and one among the PR patients. Fourteen percent of the alleles found among patients of Italian origin were R1162X, and 7% were 2183AA®G mutations. These mutations, together with DF508, were also studied in a sample of 270 normal non-related subjects of Italian origin who have been born in PR. In this sample we found two DF508 alleles and one 2183AA®G allele. DF508, R1162X and 2183AA®G frequencies were not statistically different from those observed in Italy. Our results demonstrate that it is important to include these mutations in southern Brazilian surveys of cystic fibrosis patients, especially when they are of Italian descent.Realizou-se a análise de 79 pacientes provenientes do Sul do Brasil para duas mutações raras da fibrose cística (CF), R1162X e 2183AA®G; dentre estes pacientes, 49 eram nascidos no Estado do Paraná (PR) e 30 eram nascidos no Estado de Santa Catarina (SC). Para a mutação 2183AA®G, dois alelos foram detectados entre os pacientes de SC e um alelo nos pacientes de PR. Para a mutação R1162X, seis alelos foram detectados entre os pacientes de SC e um alelo entre os pacientes do PR. Quando estes pacientes foram classificados de acordo com a origem étnica, 14% dos alelos detectados entre os pacientes de origem italiana eram portadores da mutação R1162X e 7% da mutação 2183AA®G. Estas mutações, juntamente com a mutação DF508, também foram analisadas em uma amostra de 270 indivíduos normais de origem italiana não-consangüíneos, os quais eram nascidos no Estado do PR. Nessa amostra foram detectados dois alelos DF508 e um alelo 2183AA®G. As freqüências das mutações DF508, R1162X e 2183AA®G não mostraram desvio estatístico significativo daquelas freqüências observadas no norte da Itália. Nossos resultados demonstram que é importante incluir estas mutações no conjunto de mutações a serem pesquisadas nos pacientes com FC do sul do Brasil, especialmente quando estes pacientes tiverem origem italiana.

We describe a patient who had difficulty in walking since toddling stage and presented proximal upper and lower member weakness which have evolved to a progressive limitation of neck and trunk flexure, compatible with rigid spine syndrome. The serum muscle enzymes were somewhat elevated and the electromyography showed a myopatic change. The muscle biopsy demonstrated an active and chronic myopathy. The DNA analysis through PCR did not display any abnormality for dystrophin gene. The dystrophin by immnofluorescence was present in all fibers, but some interruptions were found in the plasma membrane giving it the appearance of a rosary. The test for merosin was normal.

A doença de Kennedy (DK) é forma rara de doença do neurônio motor caracterizada por mutação na região codificadora do gene do receptor androgênico localizado no braço longo do cromossoma X (Xq 11-12). Há expansão das sequências de trinucleotídeos CAG que nos pacientes deve atingir número maior do que 347 repetições de pares de bases. Apresentamos quatro gerações de uma família com dez indivíduos acometidos. Avaliamos três pacientes do sexo masculino com idade variando entre 50 e 60 anos que desenvolveram sintomatologia por volta de 30 anos de idade caracterizada por fraqueza muscular progressiva associada a disfagia e disartria. O exame demonstrou ginecomastia, atrofia testicular, amiotrofia, fasciculações, paresia, abolição de reflexos e tremor postural. A análise do DNA pela técnica do PCR demonstrou número de repetições CAG aumentado no locus Xq 11-12 nos três pacientes e em uma mulher assintomática da família. Demonstramos a primeira família brasileira com diagnóstico de DK através de genética molecular. A DK deve fazer parte do diagnóstico diferencial das doenças do neurônio motor e a identificação destes pacientes é importante para o prognóstico e para o aconselhamento genético.

A missense G209A mutation of the alpha-synuclein gene was recently described in a large Contursi kindred with Parkinson's disease (PD). The objective of this study is to determine if the mutation G209A of the alpha-synuclein gene was present in 10 Brazilian families with PD. PD patients were recruited from movement disorders clinics of Brazil. A family history with two or more affected in relatives was the inclusion criterion for this study. The alpha-synuclein G209A mutation assay was made using polymerase chain reaction and the restriction enzyme Tsp45I. Ten patients from 10 unrelated families were studied. The mean age of PD onset was 42.7 years old. We did not find the G209A mutation in our 10 families with PD. Our results suggest that alpha-synuclein mutation G209A is uncommon in Brazilian PD families.Recentemente foi detectada mutação missense G209A no gene da alfa-sinucleína em uma grande família com doença de Parkinson (DP) de Contursi, Itália. Este estudo tem o objetivo de determinar se a mutação G209A está presente em 10 famílias brasileiras com DP. Pacientes com DP foram recrutados em clínicas de distúrbio do movimento no Brasil. O critério de inclusão no estudo foi à presença de dois ou mais familiares acometidos pela DP. A mutação G209A do gene da alfa-sinucleína foi pesquisada usando a técnica de reação em cadeia de polimerase e a enzima de restrição Tsp45I. Foram estudados 10 pacientes de famílias não-relacionadas. A idade média do início dos sintomas da DP foi 42,7 anos. Não encontramos a mutação estudada neste grupo de pacientes. Nossos resultados sugerem que a mutação G209A é incomum em famílias brasileiras com DP.

We have identified a large expansion of an ATTCT repeat within intron 9 of ATXN10 on chromosome 22q13.31 as the genetic mutation of spinocerebellar ataxia type 10 (SCA10). Our subsequent studies indicated that neither a gain nor a loss of function of ataxin 10 is likely the major pathogenic mechanism of SCA10. Here, using SCA10 cells, and transfected cells and transgenic mouse brain expressing expanded intronic AUUCU repeats as disease models, we show evidence for a key pathogenic molecular mechanism of SCA10. First, we studied the fate of the mutant repeat RNA by in situ hybridization. A Cy3-(AGAAU)(10) riboprobe detected expanded AUUCU repeats aggregated in foci in SCA10 cells. Pull-down and co-immunoprecipitation data suggested that expanded AUUCU repeats within the spliced intronic sequence strongly bind to hnRNP K. Co-localization of hnRNP K and the AUUCU repeat aggregates in the transgenic mouse brain and transfected cells confirmed this interaction. To examine the impact of this interaction on hnRNP K function, we performed RT-PCR analysis of a splicing-regulatory target of hnRNP K, and found diminished hnRNP K activity in SCA10 cells. Cells expressing expanded AUUCU repeats underwent apoptosis, which accompanied massive translocation of PKCdelta to mitochondria and activation of caspase 3. Importantly, siRNA-mediated hnRNP K deficiency also caused the same apoptotic event in otherwise normal cells, and over-expression of hnRNP K rescued cells expressing expanded AUUCU repeats from apoptosis, suggesting that the loss of function of hnRNP K plays a key role in cell death of SCA10. These results suggest that the expanded AUUCU-repeat in the intronic RNA undergoes normal transcription and splicing, but causes apoptosis via an activation cascade involving a loss of hnRNP K activities, massive translocation of PKCdelta to mitochondria, and caspase 3 activation.

Early-onset Huntington's disease (HD) occurs in approximately 10% of HD's cases. We report juvenile HD in phenotypically identical twins, evaluated by history, clinical and neurologic examination, mini-mental state examination, blood laboratory exams, cerebrospinal fluid examination, skull computed tomography, and genetic examination for HD. Patients had the akinetic-rigid variety (Westphal variant) of the disease and paternal inheritance. The laboratory workup confirmed the clinical diagnosis of HD, which adds this report to the rare cases of HD in twins reported in the literature.Doença de Huntington (DH) de início precoce ocorre em aproximadamente 10% dos casos de DH. Relatamos DH juvenil em gêmeas fenotipicamente idênticas, avaliadas por história, exames clínico e neurológico, mini-exame do estado mental, exames de sangue, exame do líquido cefalorraquidiano, tomografia computadorizada de crânio e exame genético para DH. As pacientes apresentavam a variedade rígido-acinética (variante de Westphal) da doença e herança paterna. A avaliação laboratorial confirmou o diagnóstico clínico de DH, acrescentando-se este relato aos raros casos de DH em gêmeos relatados na literatura.

Descrevemos uma família brasileira na qual a mãe e três filhas apresentam episódios compatíveis com migrânea, acompanhados por alteração no conteúdo da linguagem (afasia), sem paresias. Alguns aspectos relativos à genética das migrâneas são revisados. Chamamos a atenção para a necessidade de investigação genética para saber se é uma variante das formas conhecidas de migrânea, como a migrânea hemiplégica familiar.

We described a patient with clinical findings from Kennedy's disease and positive genetic study for Kugelberg-Welander's disease. A 24 years old man with negative family history presented with progressive spinal and bulbar muscular atrophy and gynecomastia at the age of 14. He was clinically diagnosed as having Kennedy's disease. However, a genetic study performed later was found to be negative for this disease and was positive for Kugelberg-Welander's disease, with deletion of the exons 7 and 8 in the "survival of motor neuron" gene.Descrevemos um paciente com achados clínicos de doença de Kennedy e estudo genético positivo para doença de Kugelberg-Welander. Homem, 24 anos e história familiar negativa, iniciou aos 14 anos com atrofia muscular espinhal de caráter progressivo com ginecomastia. Obteve diagnóstico clínico de doença de Kennedy, entretanto o estudo genético foi negativo para esta doença e positivo para doença de Kugelberg-Welander, com deleções dos exons 7 e 8 e do gene do survival of motor neuron.

CONTEXT: Leber's hereditary optic neuropathy is an important cause of progressive painless visual loss among young male patients. OBJECTIVE: To report on a case of a young patient with a clinical and neurophysiological condition suggestive of Leber's hereditary optic neuropathy, confirmed by genetic testing. CASE REPORT: We describe a 17-year-old male with progressive bilateral visual loss. Two maternal uncles had had similar patterns of visual loss. The patient had a history of smoking and alcohol abuse. Neuro-ophthalmological examination revealed visual acuity of 20/800 in both eyes, with decreased direct and consensual pupillary light reflexes. Fundus examination demonstrated pale optic discs. The visual evoked potential test showed signs of conduction disturbances in both optic nerves and campimetric study showed complete visual loss in all fields of both eyes. A diagnosis of bilateral optic neuropathy with a clinical suspicion of Leber's hereditary optic neuropathy was made. A blood sample was submitted to genetic analysis in relation to the principal mutations of this disorder, and homoplasmic mutation in 11778 was detected, thereby confirming the diagnosis of Leber's hereditary optic neuropathy.

CONTEXT Diastrophic dysplasia is a type of osteochondrodysplasia caused by homozygous mutation in the gene DTDST (diastrophic dysplasia sulfate transporter gene). Abnormalities occurring particularly in the skeletal and cartilaginous system are typical of the disease, which has an incidence of 1 in 100,000 live births. CASE REPORT The case of a pregnant woman, without any consanguineous relationship with her husband, whose fetus was diagnosed with skeletal dysplasia based on ultrasound findings and DNA tests, is described. An obstetric ultrasound scan produced in the 16th week of gestation revealed characteristics that guided the clinical diagnosis. Prominent among these characteristics were rhizomelia of the lower and upper limbs (shortening of the proximal portions) and mesomelia (shortening of the intermediate portions). Both upper limbs showed marked curvature, with the first finger of the upper limbs in abduction and clinodactyly of the fifth finger. Molecular analysis using the polymerase chain reaction (PCR) and gene sequencing detected mutations that had already been described in the literature for the gene DTDST, named c.862C > T and c.2147_2148insCT. Therefore, the fetus was a compound heterozygote, carrying two different mutations. CONCLUSIONS Prenatal diagnosis of this condition allowed a more realistic interpretation of the prognosis, and of the couple's reproductive future. This case report shows the contribution of molecular genetics towards the prenatal diagnosis, for which there are few descriptions in the literature.